New alfentanil composition for the treatment of acute pain

ABSTRACT

There is provided pharmaceutical compositions for the treatment of pain e.g. short-term pain, which compositions comprise a mixture comprising:
     (a) microparticles of alfentanil, or a pharmaceutically acceptable salt thereof, which microparticles are presented on the surfaces of larger carrier particles;   (b) a water-soluble weak base; and   (c) a compound which is a weak acid, which acid is presented in intimate mixture with the microparticles of alfentanil or salt thereof.   

     The composition may further comprise a disintegrant. The acid is preferably citric acid.

This application is a continuation, and claims the benefit under 35U.S.C. 120, of U.S. patent application Ser. No. 15/138,570, filed Apr.26, 2016, which is a continuation of and claims the benefit under 35U.S.C. 120, of U.S. patent application Ser. No. 14/331,507, filed Jul.15, 2014, now U.S. Pat. No. 9,345,698, which is a continuation, andclaims the benefit under 35 U.S.C. 120, of U.S. patent application Ser.No. 13/874,762, filed on May 1, 2013, now U.S. Pat. No. 8,815,911, whichclaims the benefit under 35 U.S.C. 119 of United Kingdom patentapplication serial no. 1207701.2 filed on May 2, 2012, and of UnitedKingdom patent application serial no. 1221130.6 filed on Nov. 23, 2012,the disclosures of which are each incorporated by reference herein intheir entireties.

This invention relates to new pharmaceutical compositions comprisingalfentanil that are useful in the treatment of pain, particularly acute,short-term pain associated with surgical, diagnostic and/or care-relatedprocedures, and may be administered transmucosally and in particularsublingually.

Opioids are widely used in medicine as analgesics. Indeed, it ispresently accepted that, in the palliation of moderate to severe pain,no more effective therapeutic agents exist.

Opioid agonist analgesics are used to treat moderate to severe, chroniccancer pain, often in combination with non-steroidal anti-inflammatorydrugs (NSAIDs), as well as acute pain (e.g. during recovery from surgeryand breakthrough pain). Further, their use is increasing in themanagement of chronic, non-malignant pain.

Additionally, invasive surgical and/or diagnostic procedures often giverise to short-lasting but nonetheless intense pain, which it isdesirable to control if possible. Painful, invasive diagnosticprocedures such as soft tissue biopsies are frequently performed,particularly on elderly patients. Painful therapeutic procedures such asorthopedic manipulations, fracture repositions, minor surgery andinvasive endoarterial interventions are frequent events in the hospitalsetting. Additionally, routine care procedures such as wound dressing,bedside examinations, turning, transportation, mobilization and variousimaging procedures are other examples where short-lasting, moderate tosevere pain is frequently reported.

Such pain is self-evidently a problem in itself. If particularlyintense, such pain, even if it is very short-lasting, can causeundesirable stress/trauma in patients. Furthermore, thefear/anticipation of such pain can in itself give rise to stress/anxietyin some patients in need of surgical and/or diagnostic procedures, andin some cases may even result on non-compliance (i.e. consent not beinggiven for the procedure). A particularly problem exists in thosepatients with a low tolerance to pain, such as children,

Moreover, for many of the above-mentioned procedures, the quality of theintervention may depend upon effective pain management.

There is thus a presently unmet clinical need for useful and reliable,short-acting product that is of use to prevention of moderate to severe,yet short-lasting, pain that is associated with painful surgical,diagnostic and/or care-related procedures.

At present, short acting analgesics and/or local anaesthetics may begiven to patients prior to such procedures, but such treatments areoften highly inconvenient. In addition to the fact that suchanaesthetics are typically given by injection (which may carry similarproblems to those identified above), residual local or systemic drug cantake several hours to wear off. Furthermore, current non-parenteraltreatment alternatives suffer from lengthy onset times and durations ofaction far beyond the actual need, resulting in unnecessaryside-effects.

International patent applications WO 00/16751, WO 2004/067004, WO2006/103418 and WO 20081068471 all disclose drug delivery systems forthe treatment of existing pain by sublingual administration, applying aninteractive mixture principle, in which the active ingredient inmicroparticulate form is adhered to the surfaces of larger carrierparticles in the presence of a bioadhesive and/or mucoadhesive promotingagent.

Prior art documents, including international patent applications WO03/005944, WO 02/067903, WO 2007/141328, WO 2010/132605, WO 01/30288 andUS patent application US 2009/0263476 Al employ pH modifying agents topromote dissolution and/or absorption of active ingredients.

European patent application EP 2114383, US patent applications US2008/0268023, US 2009/0048237 and US 2011/0091544, and internationalpatent applications WO 2007/081949 and WO 2008/085765 on the other handrelate to formulations comprising (specifically-stated) non-orderedmixtures of opioids, for example sufentanil, bioadhesive and stearicacid, which form a hydrogel in use (sublingual delivery). Internationalpatent application WO 2010/059504 relates to a sufentanil formulationcomprising oxygen scavengers in packaging to minimise degradation. Itstated in that document that the use of antioxidants, such as butylatedhydroxytoluene (BHT) in solid sufentanil formulations do not stopdegradation of the API.

Dissolvable lozenges, in which drug is embedded in a matrix, aredisclosed in US patent application US 2002/0160043 and internationalpatent application WO 91/03237. International patent application WO2008/106689 and US patent application US 2009/0011030 disclose powdersfor inhalation, but also cross-reference the fentanyl lollipop Acticpa.

Layered tablets are disclosed in international patent application WO2006/097361 and US patent application 2010/0233257. In WO 2006/097361, asingle compacted core is made from mannitol and microcrystallinecellulose (and optionally other excipients). This core is then coatedwith active ingredient (such as an opioid) in a solution or suspension.A pH-modifying component may be added at this stage. Spray-coatedformulations are also disclosed in US 2010/0233257. Compressibleinteractive mixtures are neither mentioned nor suggested in either ofthese documents.

pH dependent transport of cationic drugs has been studied (see e.g. Palmet al, J. Pharmacol. Exp. Ther., 291, 435 (1999) and Wang et al, Eur. J.Pharm, Sci., 39, 272 (2010)). US patent application 2007/0104763discloses a lozenge for intraoral delivery comprising micronizedfentanyl dispersed in a matrix comprising dextrose. US patentapplication 2009/0263476 refers to opioid-containing (e.g. fentanyl)buccal tablets in which a filler is employed, which is an alkaline metaloxide or hydroxide to improve transmucosal drug absorption. The use of,for example, magnesium oxide and magnesium hydroxide to give a higher pHis stated to enhance absorption without leading to instability of drugexhibited with other bases.

Stabilisation of drugs to oxidative degradation is discussed generallyin the review article by Waterman et al, Pharmaceutical Development andTechnology, 7, 1 (2002). US patent application 2011/0150989 alsodiscloses specific stabilised morphinan-containing granules.

Effervescent opioid containing formulations are disclosed in inter alisUS patent applications 2005/0142197, 2005/0142198, 2007/0036853 and2011/0071181. International patent application WO 99/24023 discloses asublingual tablet comprising an opioid, such morphine, mannitol andcitric acid (in addition to sodium citrate).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a comparison of chemical stability of various batches ofalfentanil-containing sublingual tablets.

FIG. 2 shows a comparison of plasma concentration-time profiles forformulations prepared as described in Example 5 below as obtained in aclinical trial.

There are currently no commercially-available solid state oral dosageformulations comprising the opioid analgesic alfentanil. It is insteadadministered intravenously as a sterile, non-pyrogenic, preservativefree aqueous solution in a concentration of 500 μg alfentanil base permL. The solution contains (as the only excipient) sodium chloride forisotonicity. To the applicant's knowledge, no short- or long-termstability issues have been reported for alfentanil solutions forinjection.

We have surprisingly found that, when attempting to formulate alfentanilinto a solid state, tablet formulation, a notable instability results.This instability is unexpectedly solved by the addition of a smallamount of weak acid, such as citric acid, provided that that acid ispresented in intimate mixture with the API.

Further, we have also found that a weak base, such as a sodiumphosphate, may also be added to such formulations to enhance absorptionand, even more surprisingly, that:

-   -   (a) the presence of the weak base does not, as expected, have a        detrimental effect on the stability of the alfentanil in such        formulations; and    -   (b) the enhanced absorption provided by the presence of the weak        base is not, as expected, abrogated or cancelled out by the        presence of the weak acid in such formulations.

According to a first aspect of the invention there is provided apharmaceutical composition suitable for sublingual delivery whichcomprises a mixture comprising:

-   -   (a) microparticles of alfentanil, or a pharmaceutically        acceptable salt thereof, which microparticles are presented on        the surfaces of larger carrier particles;    -   (b) a water-soluble weak base, such as a phosphate; and    -   (c) a compound which is a weak acid, which acid is presented in        intimate mixture with the microparticles of alfentanil or salt        thereof.        Such compositions are referred to hereinafter as “the        compositions of the invention”.

Alfentanil and pharmaceutically-acceptable salts thereof are presentedin the compositions of the invention in the form of microparticles.Microparticles preferably possess a weight based mean diameter, numberbased mean diameter and/or a volume based mean diameter of between about0.5 μm and about 30 μm, e.g. about 15 μm, such as between about 1 μm andabout 10 μm. As used herein, the term “weight based mean diameter” willbe understood by the skilled person to include that the average particlesize is characterised and defined from a particle size distribution byweight, i.e. a distribution where the existing fraction (relativeamount) in each size class is defined as the weight fraction, asobtained by e.g. sieving (e.g. wet sieving). As used herein, the term“number based mean diameter” will be understood by the skilled person toinclude that the average particle size is characterised and defined froma particle size distribution by number, i.e. a distribution where theexisting fraction (relative amount) in each size class is defined as thenumber fraction, as measured by e.g. microscopy. As used herein, theterm “volume based mean diameter” will be understood by the skilledperson to include that the average particle size is characterised anddefined from a particle size distribution by volume, i.e. a distributionwhere the existing fraction (relative amount) in each size class isdefined as the volume fraction, as measured by e.g. laser diffraction.

Microparticles of active ingredient may be prepared by standardmicronisation techniques, such as grinding, jet milling, dry milling,wet milling, precipitation, etc. An air elutriation process may beutilised subsequently to prepare specific size fractions, if required.

Preferred salts of alfentanil include hydrochloride salts.

Weakly acidic materials that may be mentioned include those that, whendissolved in water and/or saliva, enable the provision (at the site ofadministration of compositions of the invention) of a pH of betweenabout 2.0 and about 6.5. For the purpose of this invention, the termincludes substances that are safe for use in mammals, and includes weakacids, weak acid derivatives and other chemicals that convert to weakacids in viva (e.g. precursors that convert to acids in viva, by forexample being sequentially activated in accordance with properties ofthe local environment). Typical pKas of weak acids are in the range ofbetween about −1.5 (e.g. about −1.74) and about 16 (e.g. about 15.74)(e.g. see Vollhardt, Organic Chemistry (1987)). A preferred range isbetween about 1 and about 10. More preferably, the weakly acidicmaterial comprises a weak acid that is safe for human consumption, forexample a food acid, such as citric acid, tartaric acid, malic acid,fumaric acid, adipic acid, succinic acid, lactic acid, acetic acid,oxalic acid, maleic acid, ammonium chloride or a combination thereof.Preferred acids include tartaric acid and, particularly, citric acid.

Also useful in place of (and/or in addition to) weak acids are chelatingagents or sequestering agents. The term “chelating” or “sequestering”agent may be defined as any ligand that is capable of coordinating to ametal through at least two interactions. Examples of such agents includeadipic acid, succinic acid, lactic acid, oxalic acid, maleic acid, andsalts of any of these or, more preferably, hydroxypropylbetadex, oracetic acid, pentetic acid, glutamic acid, citric acid, tartaric acid,fumaric acid, edetic acid, malic acid, or salts of any of these,including calcium acetate, disodium edentate and, particularly, sodiumcitrate.

Thus, compositions of the invention may in the alternative comprise:

-   -   (a) microparticles of alfentanil, or a pharmaceutically        acceptable salt thereof, which microparticles are presented on        the surfaces of larger carrier particles;    -   (b) a water-soluble weak base, such as a phosphate; and    -   (c) a compound which is a sequestering agent, which agent is        presented in intimate mixture with the microparticles of        alfentanil or salt thereof.

In such instances, all preferred features of the invention as describedherein for, and all statements and/or references made in respect of,weak acid materials may be applied equally to sequestering agents.

To provide compositions of the invention, microparticles of alfentanilor pharmaceutically-acceptable salts thereof are presented in intimatemixture with particles of weakly acidic material. By “intimate mixture”we mean that some form of mixing step (simple mixing, granulation orotherwise) takes place as between the alfentanil/salt microparticles andparticles of weakly acidic material, rendering them in intimate contactwith each other. In this respect, as employed herein, the terms“intimate mixture” and “intimate contact” may be employedinterchangeably.

Compositions of the invention are presented in the form of a mixturecomprising carrier particles upon the surfaces of which are presented(e.g. adhered) microparticles of alfentanil or a pharmaceuticallyacceptable salt thereof. Such a mixture may be termed an interactivemixture.

Carrier particles in interactive mixtures may comprisepharmaceutically-acceptable substances that are soluble in water, suchas carbohydrates, e.g. sugars, such as lactose, and sugar alcohols, suchas mannitol, sorbitol and xylitol; or pharmaceutically-acceptableinorganic salts, such as sodium chloride. Alternatively, carrierparticles may comprise pharmaceutically-acceptable substances that areinsoluble or sparingly soluble in water, such as dicalcium phosphateanhydrate, dicalcium phosphate dihydrate, tricalcium phosphate, calciumcarbonate, and barium sulphate; starch and pre-gelatinised starch;bioadhesive and mucoadhesive materials, such as crosslinkedpolyvinylpyrrolidone and croscarmellose sodium; and other polymers, suchas microcrystalline cellulose, cellulose; or mixtures thereof.

By “soluble in water” we include that the material has a solubility inwater that is greater than 33.3 mg/mL at atmospheric pressure (e.g. 1bar) and room temperature (e.g. 21° C.). On the other hand, the term“sparingly soluble or insoluble in water” includes materials that have asolubility in water that is less than 33.3 mg/mL under the sameconditions. Preferred carrier particle materials include carbohydrates,including sugar alcohols, such as sorbitol, xylitol and, particularly,mannitol.

In order to provide intimate mixture/contact of microparticles ofalfentanil or salt thereof and particles of weakly acidic material, thelatter may be presented, for example either:

-   -   (a) within (i.e. as at least part of) said carrier particles,        such that said carrier particles comprise or consist of said        weak acid material, for example carrier particles may comprise a        composite of weak acid material and another carrier particle        material; and/or    -   (b) upon the surfaces of the carrier particles, along with the        microparticles of alfentanil or salt thereof (e.g. as part of an        interactive mixture).

In this respect, any technique may be employed that involves forcingtogether weakly acidic material and carrier particles carryingmicroparticles of alfentanil or salt thereof, for example a compactiontechnique, such as compression and/or granulation.

Although weakly acidic material may also be presented between suchcarrier particles carrying the alfentanil/salt, we have found that it isimportant that at least some (e.g. about 10%, such as about 20%, forexample about 30%, including about 40%, such as about 50%) of the weaklyacidic material that is included in a composition of the invention ispresented in intimate mixture with the alfentanil/salt, for exampleeither as part of the interactive mixture, so that it is in contact with(e.g. adhered to) the surfaces of the carrier particles, and/or withinsaid carrier particles, as described herein. We have found that, ifweakly acidic material is only presented between such carrier particlescarrying the alfentanil/salt (i.e. within the “bulk” along with thebase), in the amounts mentioned herein, the stability advantagesdiscussed herein are surprisingly not observed.

The term “interactive” mixture will be understood by those skilled inthe art to include the term “ordered” mixture, and to denote a mixturein which particles do not appear as single units, as in random mixtures,but rather where smaller particles (e.g. microparticles of, for example,alfentanil) are attached to (i.e. adhered to or associated with) thesurfaces of larger carrier particles. Such mixtures are characterised byinteractive forces (for example van der Weals forces, electrostatic orCoulomb forces, and/or hydrogen bonding) between carrier andsurface-associated particles (see, for example, Staniforth, PowderTechnol., 45, 75 (1985)). In final mixtures, and compositions comprisingsuch mixtures, the interactive forces need to be strong enough to keepthe adherent particles at the carrier surface,

When interactive mixtures are employed carrier particles may be of asize (weight and/or volume based average or mean diameter, vide supra)that is between about 30 μm and about 1000 μm (e.g. about 800 μm, suchas about 750 μm), and preferably between about 50 (such as about 100 μm)and about 600 μm (such as about 500 μm, or about 450 μm), for exampleabout 400 μm.

When employed in particulate form in intimate mixture with alfentanil orsalt thereof on the surfaces of carrier particles, suitable particlesizes of weakly acidic materials that may be employed are in the rangesdiscussed hereinbefore for alfentanil or salt thereof.

Carrier particles comprising weakly acidic materials may comprisecomposites of such materials with other carrier particle materials andmay be prepared by direct compression or granulation (wet or dry), forexample as described hereinafter. In such instances, suitable particlesizes (weight and/or volume based average or mean diameter, vide supra)of weakly acidic materials that may be employed are higher than theranges discussed hereinbefore and may be in the range of about 30 μm andabout 400 μm), and preferably between about 40 μm (such as about 50 μm)and about 200 μm (such as about 150 μm or about 100 μm).

The skilled person will appreciate that, when weak acids are employedwhich are not solids (and therefore not particulate) at or around roomtemperature and atmospheric pressure, they may be adsorbed onto aparticulate carrier material (such as silica) in order to provideparticles comprising the weakly acidic material. Such may then beemployed in intimate mixture with the alfentanil/salt or as part of acarrier composite.

Compositions of the invention further comprise a weak base, such as awater-soluble phosphate. Weak bases that may be mentioned furtherinclude those that, when dissolved in water and/or saliva, enable theprovision (at the site of administration of compositions of theinvention) of a pH of between about 7.5 and about 13.0. For the purposeof this invention, the term includes substances that are safe for use inmammals, and includes weak bases, weak base derivatives and otherchemicals that convert to weak bases in vivo (e.g. precursors thatconvert to bases in vivo, by for example being sequentially activated inaccordance with properties of the local environment). Typical pKbs ofweak bases are in the range of between about −1.5 and about 16. Apreferred range is between about 1 and about 10. More preferably, theweak base is safe for human consumption, for example a phosphate base, acarbonate base or a hydroxide base.

The term “water-soluble phosphate” is employed in the context of thepresent invention to denote a phosphate-containing inorganic salt thatis capable of dissolving in water and/or saliva to form a solution. Theterm “water-soluble” is as defined above. Preferred phosphate saltsinclude potassium and sodium phosphate salts, for example monosodiumphosphate, more preferably disodium phosphate (e.g. disodium phosphatedihydrate) and, particularly, trisodium phosphate (e.g. trisodiumphosphate anhydrous). Other bases, such as (e.g. water-soluble)carbonates, such as disodium carbonate, and hydroxides, may also beemployed instead of, or in addition to, the phosphate. In suchinstances, all preferred features of the invention as described hereinfor, and all statements and/or references made in respect of,water-soluble phosphates may be applied equally to other weak bases,including carbonates, such as disodium carbonate.

It is preferred that compositions of the invention are non-effervescent.By “non-effervescent”, we mean that, following intraoral administration,the components of the composition are not such (and/or are not presentin such amounts) that they give rise to either:

-   -   (a) the perceptible (i.e. the subject does not feel); or the        measurable (i.e. by scientific instrumentation)    -   (b) emission of bubbles of gas within saliva or other aqueous        media with a pH in the range between about 4 and about 9, such        as about 8.

The water-soluble phosphate material may be employed in solid state formin compositions of the invention. It is not necessary for the phosphateto be in intimate contact with the alfentanil or the weak acid or, forexample, part of an interactive mixture. Surprisingly, it is notnecessary for the weakly acidic material to be in contact with thephosphate base.

As mentioned previously, although it has been found that alfentanil andsalts thereof are highly stable in solution, their formulation in solidstate dosage forms such as those described herein has been foundunexpectedly to give rise to instability problems. Further,co-formulation of alfentanil and salts thereof along with water-solublephosphates in the solid state gives rise to further enhancement of suchinstability problems. This problem is solved by co-formulation with theweakly acidic material in the manner described herein.

We have found that the weak base (e.g. water-soluble phosphate) mayenhance absorption of alfentanil/salt thereof across the mucosalsurface. Furthermore, the chemical stability of the alfentanil/saltthereof in a composition of the invention may be improved if a smallamount of weak acid (e.g. up to about 1%, such as about 0.75%, such asabout 0.5%, by weight of the total weight of a composition of theinvention) is employed as described herein. The presence of a weaklyacid material, such as citric acid, would be expected to at leastpartially neutralise the absorption-enhancing effect of the weak base,but, as presented in compositions of the invention, this is not thecase. Even more surprisingly, the presence of an excess of weak base, aspresented in compositions of the invention, does not, as would beexpected, affect the stability of the alfentanil or salt thereof.

Thus, the problem of a completely unexpected observation of instabilityof alfentanil and salts thereof in solid state formulations is in itselfsolved in a counter-intuitive way: the positive effects of the acid(provision of stability in the solid state) and the base (provision ofenhanced absorption following administration) would be expected to becancelled out by their respective negative effects (i.e. reducedabsorption after administration due to the presence of acid andinstability of alfentanil in the solid state due to the presence ofbase), but this is not observed.

According to a further aspect of the invention there is provided amethod of stabilising a solid state pharmaceutical composition (e.g. atablet for sublingual administration) comprising alfentanil or apharmaceutically acceptable salt thereof, which method comprisesproviding particles of a weak acid (such as citric acid) in intimatemixture with particles of alfentanil or salt thereof. In such a method,the pharmaceutical composition may further comprise a weak base (such asa water-soluble phosphate). Such a weak base may be present in excess(by weight relative to the weak acid).

There is further provided the use of a weak acid (such as citric acid)to stabilise a solid state pharmaceutical composition (e.g. a tablet forsublingual administration) comprising alfentanil or a pharmaceuticallyacceptable salt thereof. Such a use preferably comprises providingparticles of said weak acid in intimate mixture with particles ofalfentanil or salt thereof. Preferably, the pharmaceutical compositionmay further comprise a weak base (such as a water-soluble phosphate),for example in excess (by weight relative to the weak acid).

Weak base, such as phosphate, and weak acid should preferably beemployed to ensure that, following administration of a formulation ofthe invention, the pH that is achieved e.g. sublingually is weaklybasic, in the range of about 7 to about 9, such as to about 8. This willdepend an the nature of the phosphate (or other weak base) that isemployed and suitable weight ratios that may be employed may be no lessthan about 1:1 (base, e.g. phosphate, to acid), such as about 2:1, forexample about 4:1, such as about 10:1, e.g. no less than about 50:1. Iftrisodium phosphate and citric acid are employed, the ratio ispreferably between about 2:1 and about 12:1, such as about 4:1.

According to a further aspect of the invention, there is provided apharmaceutical composition comprising microparticles of alfentanil or apharmaceutically acceptable salt thereof, particles of a weak acid(which are preferably in intimate mixture with the microparticles ofalfentanil or salt thereof) and a water-soluble phosphate, wherein acidand phosphate are employed in relative amounts characterized in thecomposition to enables the provision (at the site of administration) ofa pH of between about 7.0 and about 9.0 (such as about 8.0), preferablyalong with the maintenance of pH within this range for an appropriatelength of time (e.g. up to about 5 minutes) to facilitate dissolution ofthe alfentanil microparticles, and/or absorption of alfentanil acrossthe sublingual mucosa thereafter.

Preferred amounts of trisodium phosphate (if employed) to produce a pHin the above-stated range are about 0.25% to about 4%, such as about 2%by weight based upon the total weight of a composition of the invention.Preferred amounts of citric acid (if employed) are about 0.05% to about1%, such as about 0.75% by weight based upon the total weight of acomposition of the invention.

Compositions of the invention may also comprise disintegrant and/orsuperdisintegrant materials. Such materials may be presented, at leastin part, as particles upon the surfaces of, and/or between, carrierparticles.

The disintegrant or “disintegrating agent” that may be employed may bedefined as any material that is capable of accelerating to a measurabledegree the disintegration/dispersion of a composition of the invention.The disintegrant may thus provide for an in vitro disintegration time ofabout 30 seconds or less, as measured according to e.g. the standardUnited States Pharmacopeia (USP) disintegration test method (see FDAGuidance for Industry: Orally Disintegrating Tablets; December 2008).This may be achieved, for example, by the material being capable ofswelling, wicking and/or deformation when placed in contact with waterand/or mucous (e.g. saliva), thus causing tablet formulations todisintegrate when so wetted.

Suitable disintegrants (as defined in, for example, Rowe et al, Handbookof Pharmaceutical Excipients, 6th ed. (2009)) include cellulosederivatives such as hydroxypropyl cellulose (HPC), low substituted HPC,methyl cellulose, ethyl hydroxyethyl cellulose, carboxymethyl cellulosecalcium, carboxymethyl cellulose sodium, microcrystalline cellulose,modified cellulose gum; starch derivatives such as moderatelycross-linked starch, modified starch, hydroxyipropyl starch andpregelatinized starch; and other disintegrants such as calcium alginate,sodium alginate, alginic acid, chitosan, docusate sodium, guar gum,magnesium aluminium silicate, polacrilin potassium andpolyvinylpyrrolidone. Combinations of two or more disintegrants may beused.

Preferred disintegrants include so-called “superdisintergrants” (asdefined in, for example, Mohanachandran et al, International Journal ofPharmaceutical Sciences Review and Research, 6, 105 (2011)), such ascross-linked polyvinylpyrrolidone, sodium starch glycolate andcroscarmellose sodium. Combinations of two or more superdisintegrantsmay be used.

Disintegrants may also be combined with superdisintegrants incompositions of the invention.

Disintegrants and/or superdisintegrants are preferably employed in an(e.g. total) amount of between 0.5 and 15% by weight based upon thetotal weight of a composition. A preferred range is from about 0.1 toabout 5%, such as from about 0.2 to about 3% (e.g. about 0.5%, such asabout 2%) by weight.

If employed in particulate form, particles of disintegrants and/orsuperdisintegrants may be presented with a particle size (weight and/orvolume based average or mean diameter, vide supra) of between about 0.1and about 100 μm (e.g. about 1 and about 50 μm).

Alternatively, disintegrants and/or superdisintegrants may also bepresent as a constituent in composite excipients. Composite excipientsmay be defined as co-processed excipient mixtures. Examples of compositeexcipients comprising superdisintegrants are Parteck® ODT, Ludipress®and Pros® Iv® EASYtab.

Bio/mucoadhesive materials may also be presented in compositions of theinvention. Such materials may be presented upon (e.g. adhered to) thesurfaces of carrier particles when components of compositions of theinvention are presented in the form of interactive mixtures.Superdisintegrant materials mentioned herein may also function asbio/mucoadhesive materials.

Compositions of the invention may be employed in the treatment and/orprophylaxis of pain. Compositions of the invention are particularlyuseful in the treatment or prophylaxis of moderate to severe and/orshort-term pain and are thus particularly useful if administered to apatient immediately before a painful diagnostic, surgical and/orcare-related procedure.

By “moderate to severe” and/or “short-term” pain, we mean pain thatcauses a degree of discomfort and/or distraction in a patient, but whichis transitory (i.e. lasts less than about an hour, such as less thanabout 30 minutes). When such pain is associated with a diagnostic,surgical or care-related procedure, it will normally lasts for only ashort period of time (e.g. a few seconds or up to about an hour)depending upon the procedure that is performed.

Alfentanil and pharmaceutically-acceptable salts thereof may be employedin a pharmacologically effective amount, which refers to an amount of anactive ingredient, which is capable of conferring a desired therapeuticeffect on a treated patient, whether administered alone or incombination with another active ingredient. Such an effect may beobjective (i.e. measurable by some test or marker) or subjective (i.e.the subject gives an indication of, or feels, an effect). Typically,subjective measurements of pain are conducted using numeric ratingscales (NFISs) and/or visual analogue scales (VASs).

Thus, appropriate pharmacologically effective amounts of alfentanil (orsalt thereof) include those that are capable of producing, and/orcontributing to the production of, the desired therapeutic effect,namely prevention/abrogation of pain, including moderate to severeand/or short-term pain, for example when administered prior to asurgical, diagnostic and/or care-related procedure.

The amounts of alfentanil/salt that may be employed in compositions ofthe invention may thus be determined by the skilled person, in relationto what will be most suitable for an individual patient. This is likelyto vary with the route of administration, the type and severity of thecondition that is to be treated, as well as the age, weight, sex, renalfunction, hepatic function and response of the particular patient to betreated.

The total amount of alfentanil/salt thereof that may be employed in acomposition of the invention may be in the range of about 0.1%, such asabout 0.5%, to about 5%, such as about 2%, by weight based upon thetotal weight of the composition. The amount of this active ingredientmay also be expressed as the amount in a unit dosage form (e.g. atablet). In such a case, the amount of alfentanil/salt that may bepresent may be sufficient to provide a dose per unit dosage form that isin the range of between about 30 μg, including about 75 μg and about 3mg (for example about 2.5 mg). A preferred range is between about 100 μgand about 2,000 μg. One, two or more dosage units may be administeredconcurrently.

Compositions of the invention, once prepared, may be administered aspowders for sublingual administration (e.g. in the case of compositionscomprising insoluble carrier particles, in the form of a spraycomprising a solvent in which the alfentanil or salt thereof is notsoluble or is poorly soluble). However, they are preferably directlycompressed/compacted into unit dosage forms (e.g. tablets) foradministration to mammalian (e.g. human) patients, for example asdescribed hereinafter.

Compositions of the invention in the form of tablets for e.g. sublingualadministration may also comprise a binder. A binder may be defined as amaterial that is capable of acting as a bond formation enhancer,facilitating the compression of the powder mass into coherent compacts.Suitable binders include cellulose gum and microcrystalline cellulose.If present, binder is preferably employed in an amount of between about2% and about 20% by weight based upon the total weight of the tabletformulation. A preferred range is from about 6% to about 20%, such asfrom about 8% to about 17% (e.g. about 12% to about 16%) by weight.

Suitable further additives and/or excipients that may be employed incompositions of the invention, in particular those in the form oftablets for e.g. sublingual administration may comprise:

-   -   (a) lubricants (such as sodium stearyl fumarate or, preferably,        magnesium stearate);    -   (b) flavourings (e.g. lemon, peppermint powder or, preferably,        menthol), sweeteners (e.g. neohesperidin, acesulfame K or,        preferably, sucralose) and dyestuffs; and/or    -   (c) other ingredients, such as colouring agents, coating        materials, preservatives and gliding agents (e.g. colloidal        silica).

Compositions of the invention may be prepared by standard techniques,and using standard equipment, known to the skilled person.

When presented in the form of interactive mixtures, particles of e.g.alfentanil/salt may be dry mixed with relevant carrier particles over aperiod of time that is sufficiently long to enable appropriate amountsof respective active ingredients to adhere to the surface of the carrierparticles. This may also apply to other active ingredients and/or any ofthe relevant excipients (e.g. weak acid) defined hereinbefore.

The skilled person will appreciate that, in order to obtain aformulation in the form of an interactive mixture by dry powder mixing,larger carrier particles must be able to exert enough force to break upagglomerates of smaller particles. This ability will primarily bedetermined by particle density, surface roughness, shape, flowabilityand, particularly, relative particle sizes.

Standard mixing equipment may be used in this regard. The mixing timeperiod is likely to vary according to the equipment used, and theskilled person will have no difficulty in determining by routineexperimentation a suitable mixing time for a given combination of activeingredient and carrier particle material(s).

Interactive mixtures may also be provided using techniques other thandry mixing, which techniques will be well known to those skilled in theart. For example, certain weak acids may be sprayed as an e.g. aqueoussolution or suspension onto the surfaces of carrier particles in orderto provide (following evaporation of the relevant solvent) particles ofthat material on the surfaces of such carrier particles.

Other ingredients may alternatively be incorporated by standard mixingor other formulation principles.

The compositions of the invention may be administered transmucosally,such as buccally, rectally, nasally or preferably sublingually by way ofappropriate dosing means known to the skilled person. A sublingualtablet may be placed under the tongue, and the active ingredientsabsorbed through the surrounding mucous membranes.

In this respect, the compositions of the invention may be incorporatedinto various kinds of pharmaceutical preparations intended fortransmucosal (e.g. sublingual) administration using standard techniques(see, for example, Lachman et al, “The Theory and Practice of IndustrialPharmacy”, Lea & Febiger, 3^(rd) edition (1986) and “Remington: TheScience and Practice of Pharmacy”, Gennaro (ed.), Philadelphia Collegeof Pharmacy & Sciences, 19^(th) edition (1995)).

Pharmaceutical preparations for sublingual administration may beobtained by combining compositions of the invention with conventionalpharmaceutical additives and/or excipients used in the art for suchpreparations, and thereafter preferably directly compressed/compactedinto unit dosage forms (e.g. tablets). (See, for example, PharmaceuticalDosage Forms: Tablets. Volume 1, 2nd Edition, Lieberman et al (eds.),Marcel Dekker, New York and Basel (1989) p. 354-356 and the documentscited therein.) Suitable compacting equipment includes standardtableting machines, such as the Kilian SP300, the Korsch EK0, the KorschXP1, the Korsch XL100, the Korsch PharmaPress 800 or the ManestyBetapress.

Suitable final sublingual tablet weights are in the range of about 5 toabout 300 mg, such as about 10 (e.g. about 50) to about 200 mg, forexample about 30 to about 175 mg, more preferably between about 30 (e.g.about 40) and about 150 (e.g. about 140 mg). Two or more tablets may betaken simultaneously. Suitable final tablet diameters are in the rangeof about 3 to about 12 mm, for example about 4 to about 10 mm, and morepreferably about 5 to about 9 mm. Suitable final tablet thicknesses arein the range of about 0.5 mm to about 6 mm, such as about 1.5 mm toabout 3 mm. Various tablet shapes are possible (e.g. circular,triangular, square, diamond, polygon or oval).

Irrespective of the foregoing, compositions of the invention comprisingdisintegrants, bioadhesives (or other excipients that function byswelling) should be essentially free (e.g. less than about 20% by weightbased on the total weight of the formulation) of water. It will beevident to the skilled person that “premature” hydratisation willdramatically decrease the performance of a tablet formulation in use andmay result in premature dissolution of active ingredients.

Wherever the word “about” is employed herein in the context ofdimensions (e.g. tablet sizes and weights, particle sizes etc.), surfacecoverage (e.g. of carrier particles by particles of active ingredients),amounts (e.g. relative amounts of individual constituents in acomposition or a component of a composition and absolute doses(including ratios) of active ingredients and/or excipients),temperatures, pressures, times, pH values, pKa values concentrations,etc., it will be appreciated that such variables are approximate and assuch may vary by ±10%, for example ±5% and preferably ±2% (e.g. ±1%)from the numbers specified herein. Wherever the word “about” is employedherein in the context of pharmacokinetic properties (C_(max), t_(max),AUCs),etc., it will be appreciated that such variables are approximateand as such may vary by ±15%, such as ±10%.

Compositions of the invention may be administered by way of appropriatedosing means known to the skilled person. For example, a sublingualtablet may be placed under the tongue, and the active ingredientsabsorbed through the surrounding mucous membrane.

Compositions of the invention may give rise to absorptioncharacteristics for alfentanil in an entirely unexpected, andpharmaceutically useful, way. For example, compositions of the inventioncompared to a prior art formulation comprising fentanyl may exhibit amuch faster onset of action, and/or a much higher bioavailability, beingobserved for compositions of the invention. This renders compositions ofthe invention extremely well suited to the planned indication (e.g. ashort acting and fast eliminating pain relief product).

According to a further aspect of the invention, there is furtherprovided a method of treatment of pain, such as moderate to severeand/or short-term pain, which method comprises sublingual administrationto a human patient in need of such treatment of a pharmaceuticalcomposition comprising between about 30 μg and about 3,000 μg (e.g.between about 100 μg and about 2,000 μg) of alfentanil or apharmaceutically acceptable salt thereof, wherein said administrationgives rise to a plasma concentration-time curve after saidadministration that possesses:

-   -   (a) t_(max) (time to maximum plasma concentration) that is        between about 5 (e.g. about 10) and about 25 minutes after said        administration; and/or    -   (b) a t_(last) (time to last measurable plasma concentration)        that is not more than about 480 minutes (e.g. about 300 minutes)        after said administration; and, optionally,    -   (c) a C_(max) (maximum plasma concentration) that is between        about 1 (e.g about 10) and about 100 μg per mL of plasma.

Such a method may further give rise to a plasma concentration-time curveafter said administration that possesses a C_(max) coefficient ofvariation of less than about 40%.

For a pharmaceutical composition comprising about 700 μg of alfentanilor a pharmaceutically acceptable salt thereof, such a method may furthergive rise to a plasma concentration-time curve after saidadministration, that possesses:

-   -   (a) an AUC (area under the plasma concentration-time curve) from        time zero up to about 30 minutes after administration (so        representing the systemic absorption during the early absorption        phase) of about 150 ng.min/mL; and/or    -   (b) an AUC from time zero up to the last concentration        extrapolated to infinity based on the elimination rate constant        (AUG) mf) of about 1,500 ng.min/mL; and/or    -   (c) an AUC coefficient of variation of less than about 50%.        (The skilled person will appreciate that the above-mentioned        AUC-related values (a) to (c) will increase/decrease        proportionally if the dose of alfentanil/salt is correspondingly        increased/decreased from about 700 μg.)

Further, the absolute bioavailability of alfentanil when administeredsublingually in a composition of the invention may be about 70% and/orabout 40% may be absorbed within the first hour.

Methods according to the invention may be employed to treat or preventpain, particularly moderate to severe pain, which may be short actingand/or associated with a diagnostic, surgical and/or care-relatedprocedure. In the latter case, compositions of the invention may beadministered immediately before (e.g. not more than about 20 minutes,such as between about 5 and about 10 minutes, prior to) said diagnostic,surgical and/or care-related procedure.

Such methods may comprise administration of a composition of theinvention as defined herein.

By “treatment” of pain, including moderate to severe and/or short-term(or short-lasting) pain, which may or may not be associated withdiagnostic, surgical and/or care-related procedures), we include thetherapeutic treatment, as well as the symptomatic and palliativetreatment. However, by “treatment” of pain associated with a diagnosticand/or surgical procedure, we also mean the prevention or prophylaxis ofthe pain that would otherwise be associated with the diagnostic and/orsurgical procedure.

In accordance with the invention, alfentanil or salts thereof may becombined with one or more other analgesic drugs, for example opioids,which may be administered sublingually (e.g. buprenorphine) orperorally, or other peroral analgesics (e.g. NSAIDs). Alfentanil/saltsmay also be combined with sedatives (e.g. benzodiazepines) or alpha2-receptor agonists (e.g. clonidine, dexmedetomidine or ketamine).Alfentanil/salts may be combined with such other drugs either incompositions of the invention or in separate combination therapy.

The compositions of the invention are useful in the treatment of pain,such as moderate to severe and/or short-term pain, for example painassociated with painful diagnostic, surgical and/or care-relatedprocedures.

When compositions of the invention are employed to treat or prevent painassociated with a diagnostic, surgical and/or care-related procedure,compositions are preferably administered immediately before (e.g. notmore than about 20 minutes, such as between about 5 and about 10minutes, prior to) said diagnostic or surgical procedure.

The compositions of the invention enable the production of unit dosageforms that are easy and inexpensive to manufacture, and which enable therapid release and/or a rapid uptake of the active ingredient employedthrough the mucosa, such as the oral mucosa, thus enabling rapid reliefof symptoms, such as those described hereinbefore.

Compositions of the invention may also have the advantage that they maybe prepared using established pharmaceutical processing methods andemploy materials that are approved for use in foods or pharmaceuticalsor of like regulatory status.

Compositions of the invention may also have the advantage that they maybe more efficacious than, be less toxic than, be shorter acting than, bemore potent than, produce fewer side effects than, be more easilyabsorbed than, possess a better patient acceptability than, have abetter pharmacokinetic profile than, and/or have other usefulpharmacological, physical, or chemical properties over, pharmaceuticalcompositions known in the prior art, whether for use in the treatment ofpain, such as moderate to severe and/or short-term pain (e.g. painassociated with diagnostic, surgical and/or care-related procedures) orotherwise.

The invention is illustrated by way of the following examples, withreference to the attached figures, in which FIG. 1 shows a comparison ofchemical stability of various batches of alfentanil-containingsublingual tablets; and FIG. 2 shows a comparison of plasmaconcentration-time profiles for formulations prepared as described inExample 5 below as obtained in a clinical trial.

EXAMPLE 1 Alfentanil Sublingual Tablets—Granulated Carrier ParticlesCarrier Particles

Eight batches of carrier particles (employed in Tablet Batches 1 to 8 asidentified in Tables 1 and 2 below) were prepared from granulatedcarrier particles comprising citric acid anhydrous (fine granular 16/40grade, DSM, Switzerland, Basel) and mannitol (Pearlitol™ 400 DC,Roquette, Lestrem, France). The carrier particles were prepared asfollows.

Citric acid was mortared by hand using a pestle and mortar and thensieved. The fraction with particle sizes that were between 90 μm and 180μm was employed in the granulation. The citric acid and mannitol werefirstly dry mixed in a small scale intensive mixer (Braun electronictype 4261, Braun AG, Germany) for approximately 1 minute in thefollowing quantities:

-   -   (i) 0.2502 g citric acid and 199.8 g mannitol;    -   (ii) 1.2524 g citric acid and 198.8 g mannitol; and    -   (iii) 2.5109 g citric acid and 197.5 g mannitol;        These amounts were selected to provide citric acid contents in        final tablets of 0.1%, 0.5% and 1% by weight, as appropriate.

Approximately 2.5% (w/w) water was then added over approximately 1minute. The wet granulate was then dried in a heat cabinet for about 17hours at 60° C. The dried granulate was then sieved. The fraction withparticle sizes greater than 710 μm was removed from the final granulate.

Two further batches of carrier particles were prepared, one followingthe same wet granulation process but not employing any citric acid (i.e.mannitol only; 200.03 g) and a second using a dry granulation process.The first was employed to make Tablet Batch 9, and the second to makeTablet Batch 10, as identified in Tables 1 and 2 below.

Citric acid was again mortared and sieved and the fraction with particlesizes that were between 90 μm and 180 μm was employed. Citric acid(2.5492 g) and mannitol (97.48 g) were dry mixed in a tumble blender(Turbula, type T2F, WAG, Switzerland) for 15 minutes). These amountswere selected to provide a citric acid content in final tablets of 2% byweight.

Magnesium stearate (vegetable origins; 0.44 g; Peter Greven,Miinstereifel, Germany; sieved through a sieve with a size of 0.5 mm)was then added to 88.52 g of the mannitol/citric acid mixture and theblending continued for 2 minutes. The powder was compressed intobriquettes using a single punch press (Korsch EK-0) equipped with 20 mmround, flat faced, punches, to give briquettes with a width ofapproximately 1.9 mm and a crushing strength of 90 N. The briquetteswere then ground, firstly though a sieve with a size of 1,560 μm andthen through another sieve of a size 710 μm. The fraction of a sizegreater than 710 μm was discarded.

Granulated carrier (amounts presented in Table 1 below) comprising oneof the above carrier particle blends was mixed together with micronizedalfentanil hydrochloride (amounts presented in Table 1 below; JohnsonMatthey, West Deptford, N.J., US; volume based mean particle size(diameter) 2.360 μm) in a tumble blender (Turbula mixer, type T2F, WAG,Switzerland) with a 100 mL DUMA container for 20 hours at 75 rpm.

The resultant interactive mixture was than mixed together withmicrocrystalline cellulose (3.35 g; Prosolv™ SMCC 90 (particle sizespecification limits: d(10)—25-46 μm, d(50)—98-146 μm, d(90)—195-276 μm;JRS Pharma, Rosenberg, Germany]), croscarmellose sodium (0.261 g;AcDiSol™, FMC Biopolymer, Cork, Ireland; approximate particle sizearound 50 μm) and trisodium phosphate anhydrous (fine granules; 0.75 gor 1 g, in appropriate amounts to provide 3% or 4%, respectively in thefinal tablet; Budenheim, Germany) in the tumble blender for a further 30minutes.

Magnesium stearate (0.125 g; sieved through a sieve with a size of 0.5mm) was then added to this mixture and mixing continued in the tumbleblender for a further 2 minutes.

The final powder mixture was then compressed into tablets using a singlepunch press (Korsch EK-0) equipped with 6 mm round, flat faced,bevelled-edged punches, to give tablets with a final tablet weight of 70mg and a tablet crushing strength of 20 N.

Different batches of tablets were prepared as described in Table 1below.

TABLE 1 Alfentanil Alfentanil HCl Mannitol Citric acid Trisodum doseamount amount amount phosphate Batch (μg) (g) (g) (g) amount (g) 1 3500.141 20.11 0.025 1 2 700 0.281 19.97 0.025 1 3 350 0.141 20.01 0.125 14 350 0.141 20.26 0.125 0.75 5 700 0.281 19.87 0.125 1 6 700 0.281 20.120.125 0.75 7 350 0.141 19.89 0.25 1 8 700 0.281 19.74 0.25 1 9 350 0.14120.14 0 1 10 350 0.141 19.64 0.5 1

Stability studies were performed. Samples were subjected to thefollowing storage conditions +25° C./60% RH, and +40° C./75% RH, withanalysis conducted at 3 months.

50 tablets of each batch were packed as a bulk in 30 mL DUMA containerand and subjected to the following storage conditions +25° C./60% RH and+40° C./75% RH (following ICH requirements of ±2° C. and 5% RH). At 1and 3 months 10 tablets were removed from each DUMA container andanalysed for organic impurities.

Impurities resulting from degradation of alfentanil were determinedusing HPLC analysis and UV detection at 220 nm. The principlealfentanil-derived degradation products had previously been identifiedas N-phenylpropanamide, N-oxides (cis/trans) of alfentanil, andcorresponding dehydrated N-oxides.

The tablets were dissolved in ammonium acetate buffer and acetonitrileand analysed on a C18 column (2.1×150 mm, Waters Xterra) using agradient mobile phase system containing acetonitrile and ammoniumacetate buffer. Related substances were quantified as Area % of thetotal area of peaks corresponding to alfentanil (all non-alfentanilpeaks with Area %s that were greater than 0.05% were included).

Table 2 below shows a comparison of various batches after storage inlong term. The total amount of alfentanil-derived impurities ispresented as Area %.

TABLE 2 Total Total Dose Amount Amount of Impurities Impurities APICitric Phosphate (Area %) (%) Batch (μg) Acid (%) (%) 25/60 40/75 1 3500.1 4 0.07 0.90 2 700 0.1 4 0.07 0.24 3 350 0.5 4 0.06 0.28 4 350 0.5 30.06 0.39 5 700 0.5 4 0.06 0.21 6 700 0.5 3 0.06 0.18 7 350 1.0 4 0.070.06 8 700 1.0 4 0.06 0.07 9 350 0 4 0.11 1.67 10 350 2.0 4 0.15 0.15

Results after storage show a clear difference in the amount ofimpurities generated between the batch with no citric acid (Batch 9) andthe other batches. The differences between the other batches are verysmall.

EXAMPLE 2 Alfentanil Sublingual Tablets EXAMPLE 2.1 Granulated CarrierParticle Batches

Granulated carrier particles comprising citric acid anhydrous (finegranular 16/40 grade, DSM, Switzerland, Basel) or trisodium citratedihydrate (Citrique Beige, Belgium) and mannitol (Pearlitol™ 400 DC,Roquette, Lestrem, France) were prepared as follows.

Citric acid and sodium citrate were first milled using an air jet mill(Pilotmill-1; Food and Pharma Systems, Italy). Citric acid was milled tovolume-based particle sizes (D(4,3)) of 4.3 μm and 99 μm, and sodiumcitrate was milled to particle sizes of 9.6 μm, 21 μm and 94 μm.

The citric acid/citrate and mannitol were firstly dry mixed in a smallscale intensive mixer (Braun electronic type 4261, Braun AG, Germany)for approximately 1 minute in the following quantities:

-   -   (i) 0.125 g citric acid/citrate and 99.875 g mannitol for a 100        g batch (or 0.25 g citric acid and 199.75 g mannitol for a 200 g        batch); and    -   (ii) 2.502 g citric acid and 97.498 mannitol for a 100 g batch        (or 5.004 g citric acid and 194.996 g mannitol for a 200 g        batch).        These amounts were selected to provide citric acid contents in        final tablets of 0.1% and 2.0% by weight, as appropriate.

Approximately 2.5% (w/w) water was then added over approximately 30seconds. The wet granulate was then dried in a heat cabinet for about 20hours at 60° C. The dried granulate was then seived. The fraction withparticle sizes greater than 710 μm was removed from the final granulate.

Granulated carrier (20.10 g) was mixed together with micronizedalfentanil hydrochloride (0.141 g; Johnson Matthey, West Deptford, N.J.,US; volume based mean particle size diameter 2.360 μm) in a tumbleblender (Turbula mixer, type T2F, WAG, Switzerland) with a 100 mL Dumacontainer for 20 hours at 72 rpm.

The resultant interactive mixture was than mixed together withmicrocrystalline cellulose (3.33 g), croscarmellose sodium (0.361 g) andtrisodium phosphate anhydrate anhydrous (1.06 g) or disodium phosphatedihydrate (Merck KGaA, Darmstadt, Germany; 1.06 g;) in the tumbleblender for a further 30 minutes.

Magnesium stearate (0.125 g; sieved through a sieve with a size of 0.5mm) was then added to this mixture and mixing continued in the tumbleblender for a further 2 minutes.

The final powder mixture was then compressed into tablets using a singlepunch press (Korsch EK-0) equipped with 6 mm round, flat faced,bevelled-edged punches, to give tablets with a final tablet weight of 70mg and a tablet crushing strength of 20 N.

Batches of tablets were prepared as follows:

-   -   (1) citric acid (2%; D(4,3): 4.3 μm); disodium phosphate        dihydrate    -   (2) citric acid (2%; D(4,3): 99 μm); disodium phosphate        dihydrate    -   (3) sodium citrate (0.1%; D(4,3): 94 μm); disodium phosphate        dihydrate    -   (4) sodium citrate (0.1%; D(4,3): 9.6 μm); trisodium phosphate        anhydrous    -   (5) sodium citrate (2%; D(4,3): 9.6 μm); trisodium phosphate        anhydrous

EXAMPLE 2.2 Interactive Mixture Batches

Essentially the same procedure as that described in Example 2.1(b) wascarried out to prepare further batches of tablets with non-granulatedcarrier particles, but in which, instead, citric acid or sodium citrateis presented on the surfaces of mannitol carrier particles.

Mannitol (19.6 g, 19.8 g or 20.1 g depending upon how much citric acidor citrate was employed) was mixed together with micronized alfentanilhydrochloride (0.141 g) and citric acid or sodium citrate of differentparticle size distributions (0.025 g, 0.25 g or 0.5 g as appropriate, toprovide 0.1%, 0.5% and 2%, respectively of citric acid/citrate in thefinal tablets), in a tumble blender for 20 hours at 72 rpm.

The resultant interactive mixture was then mixed together withmicrocrystalline cellulose (3.33 g), croscarmellose sodium (0.361 g) andtrisodium phosphate anhydrous or disodium phosphate dihydrate (1.06 g)for a further 30 minutes.

Magnesium stearate (0.125 g; sieved through a sieve with a size of 0.5mm) was then added to this mixture and mixing continued for a further 2minutes.

The final powder mixtures were then compressed into tablets as describedin Example 2.1 above to produce batches of tablets as follows:

-   -   (6) sodium citrate (2%; D(4,3): 9.6 μm); disodium phosphate        dihydrate    -   (7) sodium citrate (0.1%; D(4,3): 94 μm); disodium phosphate        dihydrate    -   (8) sodium citrate (2%; D(4,3): 9.6 μm); disodium phosphate        dihydrate    -   (9) citric acid (0.1%; D(4,3): 4.3 μm); trisodium phosphate        anhydrous    -   (10) citric acid (2%; D(4,3): 99 μm); trisodium phosphate        anhydrous    -   (11) sodium citrate (1%; D(4,3): 21 μm); trisodium phosphate        anhydrous    -   (12) sodium citrate (1%; D(4,3): 21 μm); trisodium phosphate        anhydrous

EXAMPLE 2.3 Comparative—Bulk Batches

Essentially the same procedure as that described in Example 2.2 wascarried out to prepare a further batch of tablets with citric acid orsodium citrate presented as part of the bulk (i.e. not presented on thesurfaces of mannitol carrier particles).

Mannitol (19.6 g, 19.8 g or 20.1 g depending upon how much citric acidor citrate was employed) was mixed together with micronized alfentanilhydrochloride (0.141 g) in the tumble blender for 20 hours at 72 rpm.

The resultant interactive mixture was than mixed together with citricacid or sodium citrate of different particle size distributions (0.025g, 0.25 g or 0.5 g as appropriate, to provide 0.1%, 0.5% and 2%,respectively of citric acid/citrate in the final tablets),microcrystalline cellulose (3.33 g), croscarmellose sodium (0.361 g) andtrisodium phosphate anhydrous or disodium phosphate dihydrate (1.06 g)for a further 30 minutes.

Magnesium stearate (0.125 g; sieved through a sieve with a size of 0.5mm) was then added to this mixture and mixing continued for a further 2minutes.

The final powder mixtures were then compressed into tablets as describedin Example 2.1 above to produce batches of tablets as follows:

-   -   (13) citric acid (0.1%; D(4,3): 4.3 μm); disodium phosphate        dihydrate    -   (14) citric acid (0.1%; D(4,3): 99 μm); disodium phosphate        dihydrate    -   (15) sodium citrate (2%; D(4,3): 94 μm); trisodium phosphate        anhydrous    -   (16) sodium citrate (1%; D(4,3): 21 μm); trisodium phosphate        anhydrous    -   (17) sodium citrate (1%; D(4,3): 21 μm); trisodium phosphate        anhydrous    -   (18) sodium citrate (1%; D(4,3): 21 μm); trisodium phosphate        anhydrous    -   (19) sodium citrate (2%; D(4,3): 9.6 μm); disodium phosphate        dihydrate

EXAMPLE 2.4 Stability Studies

Stability studies were performed on Batches 1 to 19 above, Samples weresubjected to +40° C./75% RH, with analysis conducted at 4 weeks.

Analysis was carried out substantially as described in Example 1 above.

Table 3 below shows a comparison of various batches after 4 weeks. Thetotal amount of alfentanil-derived impurities is presented as Area %.

TABLE 3 Impurities Batch No. Acid/Salt Mixing Mode (Area %) 13 acid bulk0.85 14 acid bulk 1.4 2 acid granule 0.07 1 acid granule 0.06 9 acidinteractive 0.53 10 acid interactive 0.69 15 salt bulk 1.6 16 salt bulk1.7 17 salt bulk 1.9 18 salt bulk 1.9 19 salt bulk 1.6 3 salt granule0.57 4 salt granule 0.28 5 salt granule 0.22 6 salt interactive 1.7 7salt interactive 1.8 8 salt interactive 1.1 11 salt interactive 1.7 12salt interactive 1.5

The results are also presented in FIG. 1. Although is a clear trend thatintimate mixing of both citric acid or citrate with alfentanil givesbetter stability (with bulk mixing giving rise to most impurities), theeffect is more pronounced with citric acid.

EXAMPLE 3 Alfentanil Sublingual Tablets

Tablets comprising a 700 μg dose of alfentanil hydrochloride wereprepared in accordance with the procedure described in Example 1 asfollows:

-   -   (a) Citric acid was mortared and sieved. The fraction with        particle sizes that were less than 180 μm was employed in the        granulation. The citric acid (7.5 g) and mannitol (592.5 g) were        dry mixed in a small scale intensive mixer (Philips HR 775,        Philips, Netherlands). The amounts were selected to provide a        citric acid content in final tablets of 1% by weight.

Approximately 2.5% (wlw) water was then added over approximately 2minutes, with a further 1 minute of additional massing time. The wetgranulate was then dried in a heat cabinet for about 20 hours at 60° C.The dried granulate was then seived. The fraction with particle sizesgreater than 710 μm was removed from the final granulate.

-   -   (b) Granulated carrier (279.9 g) was mixed together with        micronized alfentanil hydrochloride (3.935 g; Johnson Matthey,        West Deptford, N.J., US; volume based mean particle size        diameter 2.360 μm) in a tumble blender (Turbula mixer, type        I-57EQ, WAG, Switzerland) with a 1L stainless steel container        for 20 hours at 47 rpm.

The resultant interactive mixture was than mixed together withmicrocrystalline cellulose (46.75 g), croscarrneliose sodium (3.65 g)and trisodium phosphate anhydrous (14.0 g, Budenheim, Germany) in thetumble blender for a further 30 minutes.

Magnesium stearate (1.75 g; sieved through a sieve with a size of 0.5mm) was then added to this mixture and mixing continued in the tumbleblender for a further 2 minutes.

The final powder mixture was then compressed into tablets using a singlepunch press (Korsch XP1 I-236E0) equipped with 6 mm round, flat faced,bevelled-edged punches, to give tablets with a final tablet weight of 70mg and a tablet crushing strength of 20 N.

EXAMPLE 4 Stability Study Comparison

Stability studies were carried out on various batches of two differentalfentanil-containing formulations:

-   -   (a) sublingual 700 μg alfentanil tablets (prepared essentially        according to the methodology described in Example 3 above except        that no granulation step (a) was performed with citric acid        (i.e. only mannitol was employed in the carrier particles), and        no phosphate base was added along with the microcrystalline        cellulose and the croscarmellose sodium); and    -   (b) sublingual 700 μg alfentanil tablets (prepared essentially        according to the methodology described in Example 3 above)

Samples were subjected to various conditions as set out in Table 4below, with analysis carried out substantially as described in Example 1above (with tablets packaged in aluminium sachets; 42 tablets/sachet).Table 4 below shows a comparison for various batches of tablets ((a) and(b)) after 6 months. The total amount of alfentanil-derived impuritiesis presented as Area % (where ND means no impurities detected).

TABLE 4 Formulation Batch Storage condition Total peaks (a) (a1) 25°C./60% RH ND (a) (a2) 40° C./75% RH 1.73 (a) (a3) 25° C./60% RH 0.12 (a)(a4) 40° C./75% RH 2.05 (b) (a1) 25° C./60% RH ND (b) (a2) 40° C./75% RHND (b) (a3) 25° C./60% RH ND (b) (a4) 40° C./75% RH ND

EXAMPLE 5 Randomised, Open, Cross-Over Study to Assess thePharmacokinetics of Sublingual Alfentanil Tablet Formulations in HealthySubjects Study Design

An open label, randomised, two-way crossover Phase I study was conductedat the Karolinska Trial Alliance (KTA), Phase I Unit, KarolinskaUniversitetssjukhuset, Huddinge, M62, 141 86 Stockholm, Sweden betweenJanuary and February 2012.

The primary objective of the study was to evaluate the pharmacokinetics(PK) after administration of two different sublingualalfentanil-containing tablet formulations in single doses in twelvehealthy, unblocked (i.e. without opioid antagonist(s) having beenadministered to subjects), male and female subjects. Secondaryobjectives included assessment of safety, tolerability, taste andacceptability of the formulations.

Subjects attended a screening visit within 28 days prior to Day −1.Following screening, subjects were admitted to the Phase I Unit on themorning of Day −1 and remained resident until approximately 24 hourspost-last dose for completion of study procedures and PK blood samplingon Day 3, after which they were discharged.

To avoid any carry-over effects between treatments, the differenttreatments were administered at least 24 hours apart (Days 1 to 2),corresponding to a washout period of 16 half-lives (the half-life ofalfentanil is approximately 1.5 hours).

Main inclusion criteria were that the male or female subjects werehealthy, unblocked, aged between 18 and 45 years (inclusive), with abody mass index (BMI) between 18.5 and 29.0 kg/m² (inclusive), and aweight within 50.0 to 100.0 kg.

Approximately the same number of each gender was randomised into thestudy. The following treatments were given to each subject according toa randomised treatment sequence:

-   -   (I) sublingual 700 μg alfentanil tablets (a); and    -   (II) sublingual 700 μg alfentanil tablets (b),        both prepared essentially according to the methodology described        in Example 4 above.

Each subject participated in the study for approximately 6 weeks, fromscreening until follow-up. In treatments (I) and (II), formulations (a)and (b), respectively, were administered in single doses with a washoutperiod of 24 hours between treatments. After completion of the studyperiod, all subjects participated in an end of study visit (Visit 3), 3to 8 days after the last dose.

Primary PK Parameters

If data permitted, the following PK parameters for both sublingualtablet formulations were calculated:

-   -   C_(max) (maximum plasma concentration).    -   t_(max) (time to maximum plasma concentration).    -   AUC_(0-last) (area under the plasma drug concentration-time        curve from time zero to the time of the last quantifiable plasma        concentration).    -   AUC_(inf) (area under the plasma drug concentration-time curve        from time zero to infinity).    -   F_(rel) (relative bioavailability).

Secondary PK Parameters

-   -   t_(lag) (time immediately prior to first quantifiable        concentration following sublingual administration).    -   t_(first) (time to first quantifiable concentration).    -   t_(1/2) (terminal half-life).    -   λ_(z) (terminal elimination rate constant).    -   CL/F (apparent clearance following sublingual administration).    -   V/F (apparent volume of distribution following sublingual        administration).    -   AUC_(extr) (% AUC extrapolated from Clast to infinity).

Safety and Tolerability Variables

Safety was assessed by adverse events (AEs), laboratory safetyassessments (haematology, biochemistry and urinalysis), 12-leadelectrocardiogram (ECG), respiration rate, blood pressure (BP), pulse,body temperature and pulse oximetry (to measure arterial oxygensaturation).

Tolerability was assessed by visual review of the sublingual mucosa byan appropriately experienced physician. A questionnaire was used to askthe subjects about taste and acceptability of the sublingualformulations.

Statistical Methods

The relative bioavailability of formulation (b) relative to formulation(a) was assessed, based on the primary PK parameters C_(max),AUC_(0-last), and AUC_(inf). These were log_(e)-transformed prior to thestatistical analysis and compared using a mixed effects ANOVA model asfollows:

Log_(e)(parameters)=Treatment+Period+Sequence+Subject(Sequence)+Error

Treatment, period and sequence were included as fixed effects andsubject within sequence as a random effect in the model. Formulation(a), which is not according to the invention, was considered thereference treatment. Differences in the least squares means (LSmeans)between the two treatments and associated 90% confidence intervals weredetermined. Back-transformation provided a point estimate (geometricmean ratio of test to reference treatment) and conventional 90%confidence intervals.

The safety population and the population for taste and acceptabilityassessments included all subjects who had received at least one dose ofinvestigational medicinal product (IMP).

Summary tables and listings were provided for the safety andtolerability (local tolerability, and taste and acceptabilityquestionnaire) assessments. In general, descriptive data summaries ofcontinuous outcomes included number of subjects with observations (n),mean, standard deviation (SD), median, minimum, maximum and coefficientof variation (CV %). CV % was not presented for change from baselinedata. Categorical outcomes were summarized by number and percent ofsubjects.

Results and Conclusions

After sublingual administration, alfentanil concentrations rapidlyincreased and were maximal by around 20 and 18 minutes for bothformulations (a) and (b), respectively. In many instances, a secondarypeak was apparent after both formulations were administered.Concentrations then declined in a monophasic manner, and werepredominantly below the limit of quantification after 8 hours post-dosefor both formulations.

Systemic exposure to alfentanil, in terms of mean C_(max), AUC_(0-last)and AUC_(inf), was comparable for both formulations. For bothformulations, the percentage of AUC_(int) that was extrapolated was lessthan 9%.

The median t_(lag) for alfentanil for both formulations was 0.0333 hours(2 minutes), with quantifiable concentrations being achieved by 0.100hours (6 minutes) in all subjects. Maximal concentrations were attainedat median times of 0.33 and 0.30 hours (20 and 18 minutes) forformulation (a) and formulation (b), respectively.

For C_(max), AUC_(0-last) and AUC_(inf), the bioavailability offormulation (b) relative to formulation (a) was close to 100% and theconfidence intervals around the ratios were fully contained within thebioequivalence limits of 0.8-1.25.

Both t_(1/2) and CL/F were comparable for the two formulations, withrespective means of 1.3 hours and 31 L/h for formulation (a), and 1.2hours and 32 L/h for formulation (b). The mean V/F was slightly lowerfor formulation (b) compared to formulation (a) with respective means of46 L and 54 L.

In general, the number and frequency of treatment-emergent AEs (TEAEs)was similar after subjects had taken both formulations (10 subjects[90.9%] experiencing 25 TEAEs after treatment with formulation (a) and11 subjects [91.7%] experiencing 30 TEAEs after treatment withformulation (b)).

The most frequent TEAE by preferred term after both formulations wassomnolence. Other common TEAEs reported were: sedation, headache andfeeling hot.

The majority of TEAEs were mild or moderate. Only one subjectexperienced any severe TEAEs. Subject 8005 experienced TEAEs of severeheadache and presyncope after treatment with formulation (a).

One subject experienced a TEAE that led to discontinuation from thestudy. Subject R008 experienced the TEAE of influenza like symptomsafter treatment with formulation (b), which was assessed as not related.As a result of this TEAE, the subject discontinued from the study beforereceiving formulation (a).

Two clinically significant physical abnormalities were observed atfollow-up. One subject experienced a worsening of atopic dermatitis,which was assessed as unlikely to be related to study treatment, betweenscreening and follow-up. Another subject presented with pharyngealerythema at follow-up.

There was a slight trend towards a decrease in mean BP shortly aftertreatment with both formulations (a) and (b). Two subjects experiencedclinically significant decreases in BR No other vital signs hadclinically significant changes and all vital signs returned to baselinevalues by 4 hours post treatment with both formulations. Overall, notrends in abnormal laboratory parameters were identified. Values thatoccurred outside the reference limits at the follow-up visit werereported infrequently for all haematology and biochemistry parameters(by 5. 2 subjects), as well as for urinalysis parameters (by 3subjects). No laboratory values outside the reference limits wereassessed as clinically significant.

Both formulations were well tolerated and the taste of both wasconsidered acceptable by the majority of subjects. All subjects saidthat they would use both formulations if available commercially. Acomparison between the two mean plasma concentration-time profiles ispresented in FIG. 2 (circles—formulation (a); triangles—formulation(b)).

There were no findings in the study that raised any safety concerns.

EXAMPLE 6 Alfentanil Sublingual Tablets

Tablets comprising 700 μg and 350 μg of alfentanil hydrochloride wereprepared as follows.

Citric acid (anhydrous) was milled using an air jet mill (Pilotmill.1;Food and Pharma System, Italy). Mannitol (Pearlitol 400 DC) waspre-mixed together with different amounts of micronized citric acid in atumble blender for 2 to 3 hours. Micronised alfentanil hydrochloride wasadded to the mixture and mixed for another 20 hours.

The resultant interactive mixture was then mixed together withmicrocrystalline cellulose (Prosolv SMCC 90), croscarmellose sodium(Ac-Di-Sol) and trisodium phosphate anhydrous or disodium carbonateanhydrous for further 30 minutes.

Magnesium stearate (sieved through a sieve with a size of 0.5 mm) wasadded to the mixture and mixing continued for further 2 minutes.

The final powder mixtures were then compressed into tablets using asingle punch press (Korsch EK-0) equipped with 7 mm round, flat faced,beveled-edged punches, to give tablets with a final tablet weight of 105mg and a tablet crushing strength of 30 N. The relative percentageamounts of the various ingredients above in 105 mg tablets for thevarious batches is shown in Table 5 below.

TABLE 5 Batch 1 2 3 4 5 6 Alfentanil 0.750¹ 0.750¹ 0.380² 0.380² 0.380²0.380² hydrochloride Mannitol 82.75 82.95 83.32 83.42 83.85 83.65 Citricacid 0.40 0.20 0.20 0.10 0.20 0.40 Trisodium 1.20 1.20 1.20 1.20 — —phosphate Disodium — — — — 0.67 0.67 carbonate Silicified 13.4 13.4 13.413.4 13.4 13.4 microcrystalline cellulose Croscarmellose 1.00 1.00 1.001.00 1.00 1.00 sodium Magnesium 0.50 0.50 0.50 0.50 0.50 0.50 stearate¹Corresponds to 700 μg alfentanil base ²Corresponds to 350 μg alfentanilbase

EXAMPLE 7 Stability Study

Stability studies were carried out on tablets from the six batches ofExample 6 above.

Samples were subjected to +40° C./75% RH with analysis conducted at 3months. 26 or 36 tablets of each batch were packed in aluminium sachets.Impurities resulting from degradation of alfentanil were determinedusing HPLC as described in Example 1 above.

Table 6 below shows a comparison for various batches of tablets. Thetotal amount of alfentanil-derived impurities is presented as Area %.

TABLE 6 Batch 1 2 3 4 5 6 Total impurities 0.11 0.15 0.19 0.21 0.20 0.14

In addition, disintegration times for tablets prepared from the abovebatches (either 3 or 6 tablets in total for each batch) were determinedby a standard US Pharmacopeia method (USP35/NF30 <701>) immediatelyafter preparation (0 months) and three months after storage (3 months)under the above conditions. The results for the tablet with the longestdisintegration time (in seconds) in each batch are presented in Table 7below.

TABLE 7 Batch 1 2 3 4 5 6 0 months 14 14 14 15 16 16 3 months 11 15 1013 18 16

All tablet batches were acceptable from a stability and disintegrationtime point of view. The batches containing disodium carbonate werenon-effervescent.

1. A pharmaceutical composition suitable for sublingual delivery whichcomprises a mixture comprising: (a) microparticles of alfentanil, or apharmaceutically acceptable salt thereof, which microparticles arepresented on the surfaces of larger carrier particles; (b) awater-soluble weak base; and (c) a compound which is a weak acid, whichacid is presented in intimate mixture with the microparticles ofalfentanil or salt thereof.
 2. A formulation as claimed in claim 1,wherein particles of weakly acidic material are presented within thecarrier particles, such that said carrier particles comprise a compositeof: (i) said acid material; and (ii) another carrier particle material.3. A composition as claimed in claim 1, wherein the particles of weaklyacidic material are presented upon the surfaces of the carrierparticles.
 4. A composition as claimed in claim 1, wherein the acid iscitric acid.
 5. A composition as claimed in claim 1, wherein thewater-soluble weak base comprises a phosphate, such as trisodiumphosphate.
 6. A composition as claimed in claim 1, wherein the carrierparticles comprise mannitol.
 7. A pharmaceutical composition as claimedin claim 1, which further comprises a disintegrant.
 8. A composition asclaimed in claim 7, wherein the disintegrant is a superdisintegrantselected from croscarmellose sodium, sodium starch glycolate,crosslinked polyvinylpyrrolidone or a mixture thereof.
 9. A compositionas claimed in claim 1 which is in the form of a tablet suitable forsublingual administration.
 10. A process for the preparation of acomposition of claim 1, which comprises dry mixing carrier particleswith alfentanil or salt thereof.
 11. A process for the preparation of asublingual tablet of claim 1, which comprises directly compressing orcompacting said composition.
 12. A method of treatment of pain, whichmethod comprises administration of a composition of claim 1 to a personsuffering from, or susceptible to pain.
 13. A composition of claim 1 foruse in a method of treatment of pain.
 14. The use of a composition asdefined in claim 1 for the manufacture of a medicament for a method oftreatment of pain.
 15. A method as claimed in claim 12, wherein the painis moderate to severe pain.
 16. A composition as claimed in claim 13,wherein the pain is moderate to severe pain.
 17. A use as claimed inclaim 14, wherein the pain is moderate to severe pain.
 18. A method asclaimed in claim 15, wherein the treatment is short term.
 19. Acomposition as claimed in claim 16, wherein the treatment is short term.20. A use as claimed in claim 17, wherein the treatment is short term.21. A method as claimed in claim 15, wherein the pain is associated witha diagnostic, a surgical or a care-related procedure.
 22. A compositionas claimed in claim 16, wherein the pain is associated with adiagnostic, a surgical or a care-related procedure.
 23. A method asclaimed in claim 15, wherein the composition is administered not morethan about 20 minutes prior to the procedure.
 24. A composition asclaimed in claim 16 wherein the composition is administered not morethan about 20 minutes prior to the procedure.
 25. A method of treatmentof pain as claimed in claim 12, which method comprises sublingualadministration to a human patient in need of treatment of apharmaceutical composition comprising between about 30 μg and about3,000 μg of alfentanil or a pharmaceutically acceptable salt thereof,wherein said administration gives rise to a plasma concentration-timecurve after said administration that posseses: (I) a t_(max) (time tomaximum plasma concentration) that is between about 10 and about 25minutes after said administration; and/or (II) a t_(last) (time to lastmeasurable plasma concentration) that is not more than about 300 minutesafter said administration; and, optionally, (III) a C_(max) (maximumplasma concentration) that is between about 10 and about 100 ng per mLof plasma.
 26. A method as claimed in claim 25 which comprisesadministration of a pharmaceutical composition suitable for sublingualdelivery which comprises a mixture comprising: (a) microparticles ofalfentanil, or a pharmaceutically acceptable salt thereof, whichmicroparticles are presented on the surfaces of larger carrierparticles; (b) a water-soluble weak base; and (c) a compound which is aweak acid, which acid is presented in intimate mixture with themicroparticles of alfentanil or salt thereof.